Delta5 and delta3, 5-c-6 substituted progesterones



Unite States Patent 3,395,161 A and A -C-6 SUBSTITUTED PROGESTERONESArvin P. Shrotf, $omerville, N..I., assignor to Ortho PharmaceuticalCorporation, a corporation of New Jersey No Drawing. Filed June 7, 1965,Ser. No. 462,076 3 Claims. (Cl. 260--397.4)

ABSTRACT OF THE DISCLOSURE A -C-6 substituted progesterones areintermediates in the preparation of A -C-6 substituted progesterones.The 19-06 substituted progesterones possess high progestationalactivity, but little, if any, antiovulatory activity.

This invention relates to certain novel steroid compounds and to theprocesses for their preparation. More particularly it relates to novel A-C-6-substituted progesterones which exhibit high progestationalactivity 9 while possessing little, if any, antiovulatory activity andto the A -C-6-substituted progesterone intermediates.

The novel compounds and processes of the present invention areillustrated by the following reaction scheme:

wherein R is hydrogen or lower alkanoyl, R is methyl and ethyl, R" ishydrogen or methyl, R is lower alkyl, and n is 2 or 3.

The novel compounds of the invention are embraced by Formulae III and IVof the above reaction scheme.

The process for the preparation of the novel compounds of the inventioncomprises the following steps:

(1) The 17a-acyloxy (or hydroxy)-6a-substituted-3- alkylene thioketalsrepresented by Formula I are treated with a mixture of a carboxylic acidand trifluoro-acetic anhydride, or a carbonyl halide or carboxylicanhydride in the presence of a strong acid to give the corresponding3,5-dienethioenolether of Formula II. The opening of the thioketal groupto give the thioenol ether is described in US. S.N. 341,762 filed Jan.31, 1964.

(2) The compound of Formula II is desulfurized with Raney nickel to givethe corresponding 3,5-dien of Formula III.

(3) The thus produced 3,5-dien (III) is selectively hydrogenated in thepresence of glacial acetic acid and palladium on charcoal to give thedesired A -compound of the Formula IV.

3,395,161 Patented July 30, 1968 While the reaction scheme and processillustrated above is directed to the 17OL-Sl-1bStItllted compounds, thesame process may be used to prepare the novel A and A -6-substituted-16a-methyl progesterones starting with the appropriate3-alkylene thioketal.

The followin examples illustrate the present invention.

EXAMPLE I 3- (B-acetylthioethylthio-6-methyl-17a-acetoxypregn-3,5-dien-20-one A mixture of 2.0 g. of6a-methyl-17a-acetoxy-progesterone 3-ethylenethioketal, 5 ml. ofmethylene chloride, 5 ml. of ethyl ether, 2 ml. of acetyl chloride, and2 ml. of boron trifiuoride etherate is stirred at C. for one hour andthe resulting clear solution is poured into 200 ml of cold water. Afterneutralizing with sodium bicarbonate, the aqueous mixture is extractedwith three small portions of methylene chloride. The residue fromevaporation of the methylene chloride solution is recrystallized fromether to afford 1.8 g. of 3-(,B-acetylthioethylthio)-6-methyl-17a-acetoxypregn-3,5-dien-20-one as pale yellow prisms of meltingpoint 134135 C.

III

Analysis.Calculated for C H O S Theoretical: C, 66.60; H, 7.98. Found:C, 66.44; H, 8.09.

M Max.235, 276 mu; 5.76, 5.82, 5.90, 6.25, 8.77 ,u

EXAMPLE II 17a-acetoxy-6-methylpregn-3,20-dien-20-one Calculated for C HO Theoretical: C, 77.80; H, 9.25. Found: C, 77.61; H, 9.20.

3 Following the procedure of Example II, but starting with: r

(1 3- (fi-acetylthioethylthio)-6-ethyl-17a-acetoxypregn-3,5-dien-20-one, and (2) 3-(fi-acetylthioethylthio)-6-methyl-17a-propionoxypregn-3,5-dien-20-one,yields, respectively:

(1) 17a-acetoxy-6-ethylpregn-3,5-dien-20-one, and (2)17apropionoxy-6-methylpregn-3,5-dien-20-one.

EXAMPLE III 17a-acetoxy-6-methylpregn-5-en-20-one 1.0 g. of17a-acetoxy-6-methylpregn-3,5-dien-20-one is treated with 15.0 ml. ofglacial acetic acid and 700 mg. of palladium on charcoal. The mixture ishydrogenated at room temperature until one mole equivalent oftheoretical hydrogen is consumed. The mixture is filtered and thefiltrate is evaporated to give an oil. Repeated recrystallization fromhexane gives 17a-acetoxy-6-methylpregn-5-en- 20-one, M.P. 166-168",

gszbexaue m N.M.R. shows no vinyl protons.

Calculated for C H O Theoretical: C, 77.37; H, 9.74. Found: C, 77.39; H,10.06.

Following the procedure of Example III, but starting with:

(1) 17a-acetoxy-6-ethylpregn-3,5-dien-20-one, and (2)17ot-propionoxy-6-methy1pregn-3,5-dien-20-one,

yields, respectively;

(1) 17tX-HCCIOXY-6-GIhYIPIGgH-S-Bl'l-20-OI16, and (2)17a-propionoxy-6-methylpregn-5-en-20-one.

EXAMPLE IV 3- (fi-acetylthioethylthio) -6,1 6ot-dimethylpregn-3,S-dien-20-one 7.2 g. of 6a,16a-dimethylprogesterone 3-ethylenethioketal istreated with 75 ml. of acetic anhydride, 25 ml. of trifluoroaceticanhydride and is heated on a steam bath for one-half hour. The mixtureis poured over ice-water and is extracted with methylene chloride. Theorganic layer is washed with sodium bicarbonate, and water, is driedover sodium sulfate and is evaporated to give 6.9 g. of3-(fi-acetylthioethylthio)-6,16a-dimethylpregn-3,5- dien-20-one as abrown oil.

EXAMPLE V 6,1Ga-dimethylpregn-Ei,S-dien-ZO-one Seven teaspoonsful ofRaney nickel is added to 700 ml. of mechanically stirred acetone. Themixture is refluxed under nitrogen for one-half hour and is allowed tocool to room temperature. To this is slowly added 6.9 g. of

3 (B acetylthioethylthio) 6,16a dimethylpregn 3,5- dien-ZO-one (preparedby the method of Example 1V) dissolved in ml. of tetrahydrofuran andstirring is continued for three and one-half hours. The mixture isfiltered and the filtrate is evaporated to give a dark colored residue.The residue is chromatographed on neutral alumina and eluted with 9:1hexane-ether. Evaporation of the solvent followed by recrystallizationfrom hexane gives 6, 16a-dirnethylpregn-3,5-dien-20-one, M.P. 126,

max.

Calculated for C H O. Theoretical: C, 84.60; H, 10.50. Found: C, 84.75;H, 10.70.

EXAMPLE VI 6,16a-dimethylpregn-S-en-ZO-one wherein R is selected fromthe group consisting of hydrogen and lower alkanoyl, R is selected fromthe group consisting of methyl and ethyl, and R" is selected from thegroup consisting of hydrogen and methyl.

2. 17a-acetoxy-6-rnethylpregn-5-en-20-one.

3. 17a-hydroxy-6-methylpregn-5-en-20-one.

References Cited UNITED STATES PATENTS 3,099,655 7/ 1963 Zderic et a1260397.3

LEWIS GO'ITS, Primary Examiner.

E. G. LOVE, Assistant Examiner.

